This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic nephropathy, with the exception of the genetics of diabetic nephropathy and our participation in multicenter clinical trials, is now reported under this single project. In the last year, we demonstrated that quantitative measures of glomerular structure predict loss of kidney function in type 2 diabetes, illustrating the importance of kidney biopsy in evaluating the risk of progressive kidney disease. We also reported a striking cross-sectional relationship between measures of kidney structure and the presence of cardiovascular autonomic neuropathy. We published several papers with the NIDDK Biomarkers Consortium in the past year, including one which examined serum beta-trace protein and beta2-microglobulin as predictors of end-stage renal disease, mortality, and cardiovascular disease in the Chronic Renal Insufficiency Cohort and another that examined urine tubular markers in the same cohort. We also examined the relationship of proximal tubular injury and chronic kidney disease as assessed by urinary KIM-1 in five different cohorts. Our systems biology efforts continue to yield interesting findings, with one paper showing that an endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. In another, we found that tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications, including diabetic kidney disease. In a long-term follow-up of our losartan clinical trials, we demonstrated that early treatment with the angiotensin-receptor blocker losartan does not provide significant long-term renoprotection in type 2 diabetes. We hope to test other potential new therapies in the coming years.